Dr. Ze'ev Selzer Interview by Columnist Mervyn Rothstein

Dr. Ze'ev Seltzer

Columnist Mervyn Rothstein Interviews Dr. Ze’ev Seltzer

Dr. Ze’ev Seltzer is a co-principal investigator in the Facial Pain Research Foundation’s trigeminal neuralgia project. A professor of genetics at the University of Toronto and an award-winning scientist, he has dedicated his career to studying the neurobiology of pain and brings to the project 37 years of research. His colleagues are principal investigator Dr. Marshall Devor of the Hebrew University of Jerusalem, Israel, and Dr. Kim Burchiel, chairman of the Department of Neurological Surgery at the Oregon Health & Science University, in Portland. The project is called “In Search of a Cure ... Finding the Genes That Predispose to Trigeminal Neuralgia.” Its goal is to identify the genes that make people susceptible to TN or cause the pain, and then move toward prevention and cure.

Dr. Seltzer spoke by telephone from his office in Toronto, Canada, with Mervyn Rothstein, who was an editor and writer at The New York Times for 29 years before retiring in 2010. Mr. Rothstein is now a columnist for Playbill Magazine, where he writes the “A Life in the Theatre” column; he is also a member of the Tony Awards Nominating Committee. He has had trigeminal neuralgia since 2005.

Why did you decide to focus on pain during your career?

I got interested in the duality of the brain-mind issue even before going to study dentistry. At the time, I was not that much interested in treating people directly as much as understanding how the brain operates and how cognition is produced. Pain has always been a favorite example or a test case that neurophysiologists who were interested in the duality of the brain-mind have chosen for their study. And philosophers did so as well. I even found not long ago when going through old stuff that I still keep – love letters to my now wife – I found a letter from the age of 21 where I wrote to her exactly what I just said. Which is that I am very interested in this aspect of life and that I will aspire to make it the subject of my professional work or endeavor-to-be. I went on to study Dentistry at Hadassah Hospital in Jerusalem, and during those studies I was exposed to the late Professor Yeshayahu Leibovitz, a philosopher of the brain-mind problem. He was also a teacher at the medical school, and taught us medical biochemistry. Hearing about my interest he advised me to take a course that he taught about the brain-mind problem. I took the course and my interest grew bigger. I was debating whether to tackle the brain-mind from the perspective of the brain or that of the mind and thought that doing it from the perspective of the organic side, the hardware side of our brain, would be a better approach than dealing with it from the software side, from the mind perspective.

I studied for a master’s in neurobiology and met Marshall Devor at a conference and he told me that Patrick Wall, who at the time was the leader of pain research in the world, had just moved part-time to Jerusalem and had established a lab, and I might consider coming to do this research at their lab. Marshall was at the time a young post-doc in Patrick Wall’s lab. This is how I started. I decided that my career would be in pain research. Working with Marshall under Patrick Wall’s guidance was actually what led me to the field, which I haven’t left.

You have said that this is the most important study to be undertaken regarding trigeminal neuralgia and other painful conditions affecting the nervous system. Why do you believe this to be so?

The importance comes from the fact that up until now most approaches to studying trigeminal neuralgia have been incidental, in the sense that other drugs that were developed for other uses, such as epilepsy, ended up by pure serendipity to be found to have an effect on trigeminal neuralgia, as you know personally. There has never been an attempt to study TN properly. By that I mean there are two approaches that are used in pain research. One is to develop an experimental pain model in an animal that imitates the human pain syndrome, and study the mechanisms associated with producing pain and its maintenance and try to develop cures or palliative treatments based on what we find. We do not have to this day a model for TN, not even for most other facial pain syndromes. The other approach is to study the disease in humans and this resulted in a few clinically important treatments but not to a better understanding of the pathophysiology of TN that still puzzles us.

The approach we take now is to go to the source code, i.e. the genetic code that comprises a complete set of recipes the body uses to construct its components and systems (aka, The Book of Life), including the nervous system that produces pain, and start from there. This has never been undertaken for TN or other orofacial pains, and this is the approach that we have begun to take now, which is to try to understand what differs in the genetic code of those like you who have developed TN, and others who have not. We hope that this approach will enable us to identify the mechanisms of TN by way of the identity of the gene or genes that play a role in producing the disease. Once we know the identity of the genes that encode the proteins that engage in the production of the disease, we will then be able to tag them by way of immunocytochemistry and then identify in the brain of a mouse or a rat the types of neurons and glial cells that express those proteins. This is also expected to identify the neural pathways in the trigeminal system where these proteins are expressed. And, by changing the proteins from the normal proteins in individuals who do not have chronic pain to that form that produces the disease, to see how this triggers the disease, and then study how to blunt the gene or suppress it or substitute it or treat it. This way we will be able to either treat individuals with TN or prevent them from developing the disease from the outset by patching the genome from the earlier stage by replacing the faulty gene with one that is not causing TN. These are some of the things we aspire to get to later on once we identify the genes that are at fault.

You have also said that your research team believes that you can come up with a cure in eight years if you have the funds to complete your study. What reasons do you have for expecting such useful results?

I don’t want to be overly optimistic at this stage, but if we had the money needed right away – and I’ll come to explain what we mean by the money needed – we would then collect as many pain patients for TN as possible and compare sequence of all the letters that comprise the genome. This costs between $3,000 and $5,000 a patient. Many thousands of pain patients would be needed, and if we had the money to collect them into the study we would be able to come up with the identity of many if not all of the polymorphisms, or genetic variants, that cause the disease in TN patients.

Collecting thousands of TN patients worldwide would take a few years. Identifying the variants by sequencing their genome would take about a year, then another year to do the statistical work and some additional genetic analysis and replication experiments. From that moment onward, once we know the polymorphisms, there would be an analysis of the mechanism that enables those polymorphisms to produce the disease, as well as pharmacological research to identify druggable targets and devise drugs that could then be tested directly on individuals who carry those specific polymorphisms. Using the same genetic knowledge we would select from all those with TN, those who carry the mutations on the gene that was used to develop the drug and test the drug directly on those individuals that carry that particular, specific polymorphism. So using not only the genetic knowledge to create a drug for the appropriate targets but to select genetically the subjects for the clinical trial - is going to make the trial cheaper and shorter, and within a couple of years or less we will be able to answer the question of whether that particular drug was a happy follow-up. So in about eight years could be enough to answer questions about the first targets.

You have been studying the genetic abnormalities that predispose carriers to develop chronic pain following limb amputation and mastectomy. How does this work relate to the trigeminal neuralgia project?

Excellent question. Obviously there are differences between chronic pain following trauma or surgery (i.e., phantom limb pain or stump pain in limb amputees and after removal of the breast or its part in women with breast cancer) and trigeminal neuralgia. But both entities share similarities. And the similarities have to do with the fact that some of the drugs that are effective in TN are also effective in other forms of neuropathic pain. Which means that they operate on similar neural cell types, and pathways, similar neural mechanisms.

Therefore we believe that if we were to screen the genome of women post-mastectomy and of men and women following a limb amputation we could identify genetic variants that not only play a major role in the pain of those entities (for which we have at the moment more than 10,700 DNA samples) but also of TN (for which we will only have up to 500 samples in our present project). My team in Israel has collected about 250 Israeli veterans who lost a limb in combat, and another large team has recently completed the collection in Cambodia of 6,000 amputees who lost a limb mostly after stepping on a land mine. We also collected in Israel 650 women postmastectomy and an ex-doctoral student in my lab in Jerusalem, who is now at the University of Pittsburgh, has also collected a cohort of 650 women postmastectomy. In Toronto another team from my group collects 2,000 patients post-cardiac and thoracic surgery. Our colleagues in Germany have collected 1,200 limb amputees for this project. These huge numbers give us the statistical power to screen the whole genome and find common and rare genetic variants for neuropathic pain. Then we could go back to the TN cohort and test specifically for those genetic variants. Using the statistical power of the Cambodian, Canadian, German, Israeli and American cohorts to identify common and rare genetic variants and going back to the TN cohort to identify whether those variants play a role in trigeminal neuralgia as well, should make the Foundation’s TN genetic study more effective.

What will you learn from the genetics of TN that can be used to help patients of other diseases and disorders?

It’s the same answer, but going the other way around. Given there are shared genetic variants between TN and other facial pain syndromes as well as chronic pain syndromes post-surgery or trauma, if we found the gene or genes that are important for TN, we might go to cohorts of other neuropathic pain entities and see if that gene or other genes play a role there as well.

The Facial Pain Research Foundation is moving forward with a sense of urgency to find cures for trigeminal neuralgia and related facial pain. Why have you hitched your efforts to such a new organization in the field of pain research?

I have been in the field of pain genetics for nearly two decades and waited to see coming up an organization comprising pain patients driving science to find a cure. They have the best vested interest in seeing this field progress. If we are successful in using this approach with TN, the hope is that pain patients worldwide, suffering from many other chronic pain syndromes will organize to help solve this problem, because they are the victims, the patients, with the best interests.

As of now, unfortunately, genetic projects are very costly, and drug companies are still reluctant to invest the money. Governments are carefully watching this field grow but do not support cohort collections and do not support well enough the genetic work. This has been very, very frustrating for me and other pain geneticists worldwide, because despite the knowledge and the methodologies that are already out there, there’s a lack of funding that stops this field from growing more rapidly, as have other fields of the human genome –involving cancer and cardiovascular, neurological, psychiatric and many other diseases. They are already deep into the game, whereas we at pain genetics are still at the early stages, mainly suffering from lack of funding. Therefore, seeing pain patients taking the initiative is heart warming, because now we can really help them find a cure.

Once you discover the genes (or patterns of genes) responsible or identify the gene defects that affects a person’s vulnerability to TN pain, what “happens” next? What are the research steps that need to be taken to find the cure ... to stop the pain ... and how difficult is this process of moving from finding the cause to eliminating it?

There are tiers or levels of resolution of the genetic analysis, or genetic depth. The most appropriate or current one, for which there is already the methodology at hand, is to do genome sequencing. But this is extremely costly. Therefore, we will have to do an intermediate step that is less deep to show the Foundation that we are able to find genetic variations that are of relevance for TN – to increase the appetite of the FPR Foundation, and to prove that this is a worthy approach. We will then look into the mechanisms and identify druggable targets, as I described earlier on. So finding the genes is not the end of the road, but just the beginning.

Each day people are contacting The Facial Pain Research Foundation and telling them that the surgeries and medications they have experienced in trying to stop trigeminal neuralgia have failed . . . that their pain is even worse.

What encouraging words do you have for these people?

The disease in most likelihood is genetic. We know that this is the case because there is higher incidence of TN in certain families. So my answer to them is that the big hope now is that genetics is going to solve the problem by combining genetic knowledge with pharmacological approaches that will be more fitting for the disease.

What can you say to people to try to influence them to support the Foundation’s research efforts?

Mainly that they should understand that none of the solutions that are offered to patients nowadays are perfect. In essence they are far from being perfect. Every treatment that has been tried has side effects – whether it is cutting the trigeminal root by a knife, or drugs that are non-specific in that they affect other parts of the brain or the body. There’s always a cost. What hasn’t been tried as yet is to go back to the Book of Life, to the set of codes that construct the nervous system and produce pain in those unfortunate individuals who inherited the bad genetic variants, and identify them and try to solve the problem right from the root.